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Mapping protein changes as the heart ages
superoxide dismutase, glutathione-Stransferase, and peroxiredoxin all decreasing. To spot proteins that may make good In the authors’ analysis, the protein biomarkers for human heart failure, whose abundance increased the most cardiology researchers first need to (more than 2-fold) was the β-isoform survey how aging by itself changes the of the myosin heavy chain, a structural heart’s proteins. With this rationale, protein that can account for much of Jennifer Grant, Kevin Schey, and colthe changes in aging cardiac muscles’ leagues at the Medical University of ability to contract. South Carolina report in JPR a comCuriously, the signaling proparison between proteins from tein most strongly up-regulated young and aged rats’ hearts with age (44%) was γ-sy(2009, DOI 10.1021/pr900297f). nuclein, which is highly exCardiologists predict that pressed in the brain and has an heart failure will continue to unclear function in the heart. increase in prevalence in west“This information on new ern countries as the populaproteins highlights the usefultion ages and the rates of dianess of discovery-oriented apbetes and obesity rise. Several proaches,” says Matt Richardgroups have built models of son, a proteomics specialist at heart-failure risk, with the goal the Indiana University School of identifying patients that of Medicine. “A detailed undermay benefit from intensive standing of aging’s effects on treatment. Similar models are the heart, even independent of in the works for conditions disease, is worthwhile.” such as cardiac arrhythmias. To extend the reach of their These models use markers proteomics analysis, the ausuch as blood glucose and sethors took a database approach rum proteins that correlate to identify proteins related to with inflammation or meathose highlighted by the iTRAQ sures of oxidative stress. Proteins of an aging heart. This network includes up-regulated process. For example, an analy“There are a couple benefits proteins (red), down-regulated proteins (green), direct interactions sis of the pathways affected by to taking a proteomics apor regulation (solid lines), and indirect relationships (dashed lines). cardiac aging suggests that the proach with heart failure kinase Akt, prominent in the biomarkers,” says Grant, who regulation of apoptosis, would is now at the University of Through use of a custom iTRAQ be up-regulated with age. Wisconsin Stout. “The first is that you analysis algorithm developed by coau“This network analysis step was can get an overview of the regulatory thor John Schwacke, the team was able something that hasn’t been done much network. And the second is that you to quantify the relative expression of before, and I think it’s valuable,” says might see proteins that were previously 1040 proteins, with 117 showing Merry Lindsey, a cardiovascular biolounder the radar and identify new changing expression with age. Most gist at the University of Texas Health mechanisms.” had not been identified by previous Science Center San Antonio. Aging by itself has a noticeable effect studies. A subset was selected for conLindsey says it will be important to on heart attack survivability, and these firmation by western blot. Prominent establish the baseline differences bedifferences may be mirrored in physigroups of proteins that shift with age tween young and old hearts in the abological changes, cardiologists say. In include those involved in calcium sigsence of pathology. That way, future the rat, the left ventricle grows by 20% naling and response to oxidative stress, experiments can layer on the effects of and cardiac fibroblasts constitute more as well as metabolic enzymes and hypertension or diabetes, which are of the heart as the animal ages. Reacstructural proteins. risk factors for heart failure for many tive oxygen species increase, while Several fatty-acid-oxidation enzymes elderly people. fatty acid oxidation and ATP producwere found to fade with age, while en“I suspect this kind of work could tion decline. These baseline effects zymes involved in glycolysis increased, translate well into the clinical realm,” need to be separated out first before consistent with previous research. she says. “For the best applicability, we examining the proteins in models of The aged hearts also displayed shifts will want to look for proteins where “actively failing” hearts, Grant says. in proteins involved in responding to the differences feed over into plasma.” To unearth nuggets of information oxidative stress, with enzymes such as —Quinn Eastman that previous 2D gel approaches had
10.1021/pr9007046
not revealed, Grant and Schey, now at Vanderbilt University, used a technique called iTRAQ (isobaric tagging for relative and absolute quantitation) to modify protein samples from the left ventricles of young and aged rat hearts. The technique uniquely tags comparable samples by alkylation so that they can be analyzed side-by-side with MS.
© 2009 American Chemical Society
Journal of Proteome Research • Vol. 8, No. 9, 2009 4171
